PMID- 37018978 OWN - NLM STAT- MEDLINE DCOM- 20230425 LR - 20230425 IS - 1878-1705 (Electronic) IS - 1567-5769 (Linking) VI - 118 DP - 2023 May TI - Hyperhomocysteinemia activates NLRP3 inflammasome to cause hepatic steatosis and insulin resistance via MDM2-mediated ubiquitination of HSF1. PG - 110085 LID - S1567-5769(23)00406-X [pii] LID - 10.1016/j.intimp.2023.110085 [doi] AB - Hyperhomocysteinemia (HHcy) is associated with nonalcoholic fatty liver disease (NAFLD) and insulin resistance (IR). However, the underlying mechanism is still unknown. Recent studies have demonstrated that NLRP3 inflammasome activation plays a vital role in NAFLD and IR. Our study aimed to explore whether NLRP3 inflammasome contributed to HHcy-induced NAFLD and IR as well as dissected the underlying mechanism. C57BL/6 mice were fed a high-methionine diet (HMD) for 8 weeks to establish the HHcy mouse model. Compared with a chow diet, HMD induced hepatic steatosis (HS) and IR as well as activation of hepatic NLRP3 inflammasome. Moreover, HHcy-induced NAFLD and IR characterization disclosed that NLRP3 inflammasome activation occurred in liver tissue of HMD-fed mice, but was very marginal in either NLRP3(-/-) or Caspase-1(-/-) mice. Mechanistically, high levels of homocysteine (Hcy) up-regulated the expression of mouse double minute 2 homolog (MDM2), which directly ubiquitinates heat shock transcription factor 1 (HSF1) and consequently activated hepatic NLRP3 inflammasome in vivo and in vitro. In addition, in vitro experiments showed P300-mediated HSF1 acetylation at K298 hindered MDM2-mediated ubiquitination of HSF1 at K372, which plays important role in determining the HSF1 level. Importantly, either inhibition of MDM2 by JNJ-165 or activation of HSF1 by HSF1A reversed HMD-induced hepatic NLRP3 inflammasome, and consequently alleviated HS and IR in mice. This study demonstrates that NLRP3 inflammasome activation contributes to HHcy-induced NAFLD and IR, and further identified that HSF1 as a new substrate of MDM2 and its decrease on MDM2-mediated ubiquitination at K372 modulates NLRP3 inflammasome activation. These findings may provide novel therapeutic strategies aimed at halting HS or IR. CI - Copyright (c) 2023 Elsevier B.V. All rights reserved. FAU - Xiang, Wenjing AU - Xiang W AD - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Yang, Yang AU - Yang Y AD - Department of Pharmacy, Zhuhai People's Hospital (Zhuhai Hospital Affiliated with Jinan University), Zhuhai, 519000, China. FAU - Weng, Liangkun AU - Weng L AD - Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Ye, Zhiming AU - Ye Z AD - Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Ding, Ping AU - Ding P AD - Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Li, Huayu AU - Li H AD - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Sun, Jia AU - Sun J AD - School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China. FAU - Zeng, Cheng AU - Zeng C AD - Center for Drug Research and Development, Guangdong Pharmaceutical University, Guangzhou 510006, China; Key Specialty of Clinical Pharmacy, The First Affiliated Hospital of Guangdong Pharmaceutical University, 510699, China; Guangdong Key Laboratory of Pharmaceutical Bioactive Substances, Guangdong Pharmaceutical University, Guangzhou, 510006, China. Electronic address: zengcheng@gdpu.edu.cn. LA - eng PT - Journal Article DEP - 20230403 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - 0 (Inflammasomes) RN - 0 (NLR Family, Pyrin Domain-Containing 3 Protein) RN - 0 (Heat Shock Transcription Factors) RN - AE28F7PNPL (Methionine) RN - 0 (Hsf1 protein, mouse) RN - 0 (Nlrp3 protein, mouse) SB - IM MH - Mice MH - Animals MH - Inflammasomes/metabolism MH - *Non-alcoholic Fatty Liver Disease/metabolism MH - NLR Family, Pyrin Domain-Containing 3 Protein/metabolism MH - Heat Shock Transcription Factors/genetics/metabolism MH - *Insulin Resistance MH - *Hyperhomocysteinemia/complications/metabolism MH - Mice, Inbred C57BL MH - Liver/metabolism MH - Methionine/metabolism MH - Ubiquitination OTO - NOTNLM OT - HSF1 OT - Hyperhomocysteinemia OT - Insulin resistance OT - MDM2 OT - NLRP3 inflammasome OT - Nonalcoholic fatty liver disease COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2023/04/06 06:00 MHDA- 2023/04/25 10:20 CRDT- 2023/04/05 18:05 PHST- 2022/09/03 00:00 [received] PHST- 2023/03/14 00:00 [revised] PHST- 2023/03/21 00:00 [accepted] PHST- 2023/04/25 10:20 [medline] PHST- 2023/04/06 06:00 [pubmed] PHST- 2023/04/05 18:05 [entrez] AID - S1567-5769(23)00406-X [pii] AID - 10.1016/j.intimp.2023.110085 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 May;118:110085. doi: 10.1016/j.intimp.2023.110085. Epub 2023 Apr 3.